The global polio eradication initiative of the World Health Organisation (WHO) has made great progress. The main tool used in the program has been the live attenuated oral polio vaccine. This live attenuated vaccine has been known for many years to cause vaccine associated poliomyelitis in a small proportion of recipients or their contacts, and more recently to be able to revert to a transmissible phenotype, causing outbreaks in several parts of the world where vaccine programs have become less vigorous as polio has disappeared. Prolonged excretion of vaccine-derived polioviruses by some immunodeficient patients has also been well documented. The use of the oral polio vaccine and its ability to alter its phenotype is therefore an issue in the eradication of polio worldwide.
It would be extremely unwise to stop vaccination immediately the last wild type virus is believed to have been isolated because wild type virus may be circulating undetected due to poor surveillance in some areas. Also, immunodeficient individuals may continue to excrete virus for a very long time after vaccination and could be a source for re-emergence. Further, there may still be outbreaks caused by the oral vaccine from the last rounds of its use.
Vaccination and surveillance must therefore continue for some time after eradication of the wild type virus is declared. This requires the use of poliovirus in laboratories engaged in surveillance and in vaccine production, which will be chiefly concerned with the manufacture of inactivated poliovaccine (IPV) of the kind developed by Salk.
The Salk vaccine is based on three wild, virulent wild type strains of poliovirus namely the Mahoney (type 1 poliovirus), MEF-1 (type 2 poliovirus), and Saukett (type 3 poliovirus) strains, grown in Vero cells ex vivo (Wood et al, Biologicals 25:59-64, 1997). The wild type polioviruses are then inactivated with formalin to produce the IPV. The wild type strains currently used in IPV production are known to be paralytic in humans and are used in large amounts in IPV production. This presents a serious containment issue, which may not be easy to reconcile with the production scales required for IPV. Some interest has been expressed in using the same strains in the manufacture of inactivated vaccine as are used in the oral vaccine on the grounds that they are attenuated and therefore present less of a hazard should they escape. However, their instability on replication in humans means that they remain hazardous, and their immunogenic properties are different from those of the wild type strains currently used so that a major clinical development program would be required to develop an IPV based on these strains.
The live attenuated poliovirus vaccines developed by Sabin in the 1950s using essentially empirical procedures have been used throughout the world as live oral poliovaccines. Over the past several years, scientists have employed a number of molecular biological techniques in an attempt to elucidate the mechanism by which the neurovirulence of these vaccine strains is reduced. Most of the work has concentrated on serotypes 1 and 3. For both of these the complete nucleotide sequences of the vaccine strains have been compared with those of their neurovirulent progenitors. In the case of poliovirus type 1, the vaccine strain differs from its progenitor at 47 positions in the 7441 base genome (Nomoto et al., Proc. Natl. Acad. Sci. USA 79:5793-5797, 1982). Analogous studies on poliovirus type 3 reveal just 10 nucleotide sequence differences in the 7432 base genome between the vaccine and its progenitor strain (Stanway et al., Proc. Natl. Acad. Sci. USA 81:1539-1543, 1984).
The type 2 strain was developed from a naturally attenuated parent but analysis of a neurovirulent revertant strain, isolated from a case of vaccine-associated poliomyelitis, identified 17 differences from Sabin 2 (Pollard et al., J. Virol. 63: 4949-4951, 1989).
A model for the secondary structure of the 5′ non-coding region of the genome of poliovirus type 3 strain has previously been proposed (Skinner et al., J. Mol. Biol. 207: 379-392, 1989). As concerns domain V (nucleotides 471-538), bases at positions 471-473 and 477-483 are paired with bases at positions 538-536 and 534-528 respectively as follows:
    471       477       483... U C C ... C C A U G G A ... ... A G G ... G G U G C C U ...    538       534       528
For convenience, the paired regions are termed stem (a) (471-473/538-536) and stem (b) (477-483/534-528). Attenuated polioviruses in which a base pair of stem (a) or stem (b) of domain V is reversed are disclosed in EP-A-0383433. Attenuated polioviruses that do not have a U-G base pair or other base pair mismatch (departure from Watson-Crick base pairing) in stem (a) or (b) of domain V of the 5′ non-coding region of the poliovirus genome are described in WO98/41619 and WO 2008/017870. These attenuated polioviruses have substantially the same attenuation as, or greater attenuation than, the parent Sabin vaccine strain (so that they are safe to use) but are much more stable genetically.